Biomedical subjects

Andrew Young

Publications and source records attributed to Andrew Young.

29 records · Page 2Linked to original sources

PubMed2005

Renal effects.

Amylin bound to kidney cortex in a distinctive pattern. Binding appeared specific in that it was displaceable with amylin antagonists. It was associated with activation of cyclic AMP (cAMP), and was thereby likely to represent receptor binding and activation. Amylin's principal effects at the kidney included a stimulation of plasma renin activity, reflected in aldosterone increases at quasi-physiological amylin concentrations. It was unclear whether this was a local or a systemic effect. Other renal effects in rats included a diuretic effect and a natriuretic effect. The latter was mainly driven by the diuresis, since urinary sodium concentration did not change. Amylin had a transient effect to lower plasma potassium concentration. This effect was likely to be a consequence of activation of Na+/K+-ATPase, an action shared with insulin and catecholamines. Amylin lowered plasma calcium, particularly ionized calcium, likely due to an antiresorptive effect at osteoclasts. Immunoreactive amylin was detected in the developing kidney. It appeared to have a trophic effect in kidney, and its absence resulted in renal dysgenesis. Neurons in the subfornical organ (SFO), which has a role in fluid/electrolyte homeostasis, were potently activated by amylin. The dipsogenic and renal effects of amylin may be related to effects at the SFO.

Aldosterone↗

PubMed2005

Effects on bone.

The actions of amylin on bone have been reviewed in several publications (MacIntyre, 1992a,b; MacIntyre et al., 1991; Reid and Cornish, 1996; Tamura et al., 1992a,b; Zaidi et al., 1990a,c, 1993b). MacIntyre proposed that amylin or its derivatives or agonists would be useful for treating bone disorders, such as osteoporosis, Paget's disease, or bone loss resulting from malignancy, endocrine disorders, autoimmune arthritides, breakage and fracture, immobility and disease, or hypercalcaemia (MacIntyre, 1995).

Amyloid↗

PubMed2005

Central nervous system and other effects.

Amylin enhanced the uptake of certain amino acids, crossed the blood-brain barrier, and increased body temperature. The physiological significance of these responses is currently unclear. An effect of peripherally injected amylin to enhance weakly trained memory fitted with similar effects of other gastrointestinal peptide hormones. Centrally administered amylin reduced locomotor and exploratory behavior. Amylin administered alone was analgesic when administered peripherally, via a non-opiate pathway. When administered in combination with opiates, there was an opiate-sparing synergy.

Amyloid↗

PubMed2005

Clinical studies.

Recognizing that type 1 diabetes was characterized not only by insulin deficiency, but also by amylin deficiency, Cooper (Cooper, 1991) predicted that certain features of the disease could be related thereto, and he proposed amylin/insulin co-replacement therapy. Although the early physiological rationale was flawed, the idea that glucose control could be improved over that attainable with insulin alone without invoking the ravages of worsening insulin-induced hypoglycemia was vindicated. The proposal spawned a first-in-class drug development program that ultimately led to marketing approval by the U.S. Food and Drug Administration of the amylinomimetic pramlintide acetate in March 2005. The prescribers' package insert (Amylin Pharmaceuticals Inc., 2005), which includes a synopsis of safety and efficacy of pramlintide, is included as Appendix 1. Pramlintide exhibited a terminal t1/2, in humans of 25-49 min and, like amylin, was cleared mainly by the kidney. The dose-limiting side effect was nausea and, at some doses, vomiting. These side effects usually subsided within the first days to weeks of administration. The principal risk of pramlintide co-therapy was an increased probability of insulin-induced hypoglycemia, especially at the initiation of therapy. This risk could be mitigated by pre-emptive reduction in insulin dose. Pramlintide dosed at 30-60 microg three to four times daily in patients with type 1 diabetes, and at doses of 120 microg twice daily in patients with type 2 diabetes, invoked a glycemic improvement, typically a decrease in HbA1c of 0.4-0.5% relative to placebo, that was sustained for at least 1 year. This change relative to control subjects treated with insulin alone typically was associated with a reduction in body weight and insulin use, and was not associated with an increase in rate of severe hypoglycemia other than at the initiation of therapy. Effects observed in animals, such as slowing of gastric emptying, inhibition of nutrient-stimulated glucagon secretion, and inhibition of food intake, generally have been replicated in humans. A notable exception appears to be induction of muscle glycogenolysis and increase in plasma lactate.

Amyloid↗

PubMed2005

Distribution of cytokeratins and vimentin in adult renal neoplasms and normal renal tissue: potential utility of a cytokeratin antibody panel in the differential diagnosis of renal tumors.

Adult renal epithelial neoplasms (RENs) comprise several distinct clinicopathologic entities with potential prognostic and therapeutic differences. Individual cases can show overlapping morphologic features, necessitating the use of ancillary methods. The purpose of this study was to determine the diagnostic utility of cytokeratin (CK) subtype expression pattern in a wide range of adult RENs. RENs (including clear cell [conventional] renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, renal oncocytoma, collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), urothelial carcinoma, metanephric adenoma (MA), tubulocystic carcinoma (TC) (also known as low-grade collecting duct carcinoma), and mucinous tubular and spindle cell carcinoma) were immunostained for CK subtypes (CK5/CK6, 7, 8, 13, 14, 17, 18, 19, 20), high molecular weight CKs 1, 5, 10, 14 (HMWCK), and vimentin (Vim). The expression pattern of normal kidney was also examined and correlated with RENs. Although there is some overlap, subtypes of RENs show distinctive CK expression profiles that may be useful in several differential diagnostic settings. Clear cell RCCs typically showed a restricted expression pattern of CK8, CK18 and Vim. Papillary RCCs typically expressed CK7, CK8, CK18, CK19, and Vim and could be distinguished from MA (CK7-). Chromophobe RCCs were typically CK7+, CK8+, CK18+, and Vim-, and could be distinguished from oncocytomas (typically CK7-). In oncocytomas, nonspecific staining of unblocked endogenous biotin is a potentially significant diagnostic pitfall. CDC, RMC, and TC demonstrated similar CK expression profiles (with the exception of HMWCK expression limited to CDC), supporting a close relationship between these entities. A panel of CK5/CK6, CK17, and Vim may be helpful in distinguishing CDC (typically CK5/CK6-, CK17-, Vim+) and urothelial carcinoma (typically CK5/CK6+, CK17+, Vim-). In conclusion, CK expression patterns may be helpful in several differential diagnostic situations when dealing with adult RENs.

Adult↗

PubMed2003

Acquired theory of mind impairments in individuals with bilateral amygdala lesions.

Studies in humans suggest that the amygdala plays a role in processing social information. A key component of social information processing is what developmental psychologists call "theory of mind": the ability to infer others' mental states. Recent studies have raised the possibility that the amygdala is involved in theory of mind, showing amygdala activation during a theory of mind task, or showing impairment on theory of mind tasks in a patient with amygdala damage acquired in childhood. Here, we present the first evidence of theory of mind deficits following amygdala damage acquired in adulthood. Two participants, D.R. and S.E., with acquired bilateral amygdala damage showed difficulties with two theory of mind tasks, "Recognition of Faux Pas" (for D.R., z=-5.17; for S.E., z=-1.83) and "Reading the Mind in the Eyes" (for S.E., z=-1.91; for D.R., z=-1.4). The items on which D.R. and S.E. made errors on these tasks were uncorrelated with the items that control participants found most difficult, indicating that these deficits cannot be attributed solely to the cognitive difficulty of the tasks. These results indicate that the amygdala's critical role in theory of mind may not be just in development, but also in "on-line" theory of mind processing in the adult brain.

Aged↗

PubMed2003

Contribution of spinal glutamatergic mechanisms in heterosegmental antinociception induced by noxious stimulation.

We evaluated the role of spinal glutamate and substance P receptors in noxious stimulus-induced antinociception (NSIA). NSIA was produced by subdermal capsaicin administration in the hind paw of the rat and measured as attenuation of the jaw-opening reflex. NSIA was completely blocked by spinal intrathecal administration of the selective NMDA receptor antagonist LY235959 as well as the mGluR5 antagonists MPEP and SIB-1757 and partially attenuated by the selective AMPA/kainate receptor antagonist NBQX; however, neither the mGluR1 receptor antagonist LY367385 nor the NK1 antagonist L-703,606 affected NSIA. These results suggest that NSIA depends on glutamate, released from the central terminals of the primary afferent nociceptors, acting primarily on NMDA and mGluR5 receptors. Although substance P is also known to be released by similar stimuli, NK1 receptors do not appear to play a role in NSIA. The implications of these findings in the context of a proposed spinal circuit that mediates NSIA are discussed.

Animals↗

PubMed2003

Chronic EtOH administration alters liver Mg2+ homeostasis.

Ethanol (EtOH) administration to rats for 4 wk markedly decreased Mg(2+) content in several tissues, including liver. Total cellular Mg(2+) accounted for 26.8 +/- 2.4 vs. 36.0 +/- 1.4 nmol Mg(2+)/mg protein in hepatocytes from EtOH-fed and control rats, respectively, and paralleled a 13% decrease in cellular ATP content. Stimulation of alpha(1)- or beta-adrenergic receptor or acute EtOH administration did not elicit an extrusion of Mg(2+) from liver cells of EtOH-fed rats while releasing 5% of total tissue Mg(2+) content from hepatocytes of control rats. Despite the 25% decrease in Mg(2+) content, hepatocytes from EtOH-fed rats did not accumulate Mg(2+) following stimulation of protein kinase C signaling pathway, whereas control hepatocytes accumulated approximately 2 nmol Mg(2+). mg protein(-1). 4 min(-1). Together, these data indicate that Mg(2+) homeostasis and transport are markedly impaired in liver cells after prolonged exposure to alcohol. The inability of liver cells, and possibly other tissues, to accumulate Mg(2+) can help explain the reduction in tissue Mg(2+) content following chronic alcohol consumption.

Adrenergic Agonists↗

PubMed2002

Alterations of the oxygen-evolving apparatus induced by a 305Arg --> 305Ser mutation in the CP43 protein of photosystem II from Synechocystis sp. PCC 6803 under chloride-limiting conditions.

The psbC gene encodes CP43, a component of Photosystem II (PSII) in higher plants, algae, and cyanobacteria. Previous work demonstrated that alteration of an arginine residue occurring at position 305 to serine produced a strain (R305S) with altered PSII activity (Knoepfle, N., Bricker, T. M., and Putnam-Evans, C. (1999) Biochemistry 38, 1582-1588). This strain grew at wild-type rates in complete BG-11 media (480 microM chloride) and evolved oxygen at rates that were 60-70% of the observed wild-type rates. The R305S strain assembled approximately 70-80% of the functional PSII centers contained in the control strain, and these PSII centers were very sensitive to photoinactivation at high light intensities. We recently observed that the R305S mutant exhibited a pronounced chloride effect. When this mutant was grown in media depleted of chloride (30 microM chloride), it exhibited a severely reduced photoautotrophic growth rate. The effect of chloride depletion on the growth rate of the mutant was reversed by the addition of 480 microM bromide to the chloride-depleted BG-11 media. Oxygen evolution rates for the mutant were further depressed to about 22% of that observed in control cells under chloride-limiting conditions. Addition of bromide restored these rates to those observed under chloride-sufficient conditions. The mutant exhibited a significantly lower relative quantum yield for oxygen evolution than did the control strain, and this was exacerbated under chloride-limiting conditions. Fluorescence yield measurements indicated that both the mutant and the control strains assembled fewer PSII reaction centers under chloride-limiting conditions. The reaction centers assembled by the mutant exhibited an enhanced sensitivity to photoinactivation under chloride-limiting conditions, with a t(1/2) of photoinactivation of 2.6 min under chloride-limiting conditions as compared to a t(1/2) of 4.7 min under normal growth conditions. The mutant also exhibited an enhanced stability of its S(2) state and increased number of centers in the S(1) state following dark incubation. These results indicate that the mutant R305S exhibits a defect in its ability to utilize chloride in support of efficient oxygen evolution in PSII. This is the first mutant of this type described in the CP43 protein.

Arginine↗

PubMed2002

Introduction of the 305Arg-->305Ser mutation in the large extrinsic loop E of the CP43 protein of Synechocystis sp. PCC 6803 leads to the loss of cytochrome c(550) binding to Photosystem II.

CP43, a component of Photosystem II (PSII) in higher plants, algae and cyanobacteria, is encoded by the psbC gene. Previous work demonstrated that alteration of an arginine residue occurring at position 305 to serine produced a strain (R305S) with altered PSII characteristics including lower oxygen-evolving activity, fewer assembled reaction centers, higher sensitivity to photoinactivation, etc. [Biochemistry 38 (1999) 1582]. Additionally, it was determined that the mutant exhibited an enhanced stability of its S2 state. Recently, we observed a significant chloride effect under chloride-limiting conditions. The mutant essentially lost the ability to grow photoautotrophically, assembled fewer fully functional PSII reaction centers and exhibited a very low rate of oxygen evolution. Thus, the observed phenotype of this mutation is very similar to that observed for the Delta(psb)V mutant, which lacks cytochrome c550 (Biochemistry 37 (1998) 1551). A His-tagged version of the R305S mutant was produced to facilitate the isolation of PSII particles. These particles were analyzed for the presence of cytochrome c550. Reduced minus oxidized difference spectroscopy and chemiluminescence examination of Western blots indicated that cytochrome c550 was absent in these PSII particles. Whole cell extracts from the R305S mutant, however, contained a similar amount of cytochrome c550 to that observed in the control strain. These results indicate that the mutation R305S in CP43 prevents the strong association of cytochrome c550 with the PSII core complex. We hypothesize that this residue is involved in the formation of the binding domain for the cytochrome.

Arginine↗

PubMed2002

Differential expression between pilocytic and anaplastic astrocytomas: identification of apolipoprotein D as a marker for low-grade, non-infiltrating primary CNS neoplasms.

Fibrillary astrocytoma, the most common primary central nervous system neoplasm, is infiltrating, rapidly proliferating, and almost invariably fatal. This contrasts with the biologically distinct pilocytic astrocytoma, which is circumscribed, often cystic, slowly proliferating, and associated with a favorable long-term outcome. Diagnostic markers for distinguishing pilocytic astrocytomas from infiltrating anaplastic astrocytomas are currently not available. To identify genes that might either serve as markers or explain these distinct biologic behaviors, cDNA microarray analysis was used to compare the expression of 7,073 genes (nearly one quarter of the human genome) between these 2 types of astrocytoma. Messenger RNAs pooled from 3 pilocytic astrocytomas and from 4 infiltrating anaplastic astrocytomas were compared. Apolipoprotein D (apoD), which expressed 8.5-fold higher in pilocytic astrocytomas, showed the greatest level of differential expression and emerged as a potential marker for pilocytic tumors. By immunohistochemistry, 10 of 13 pilocytic astrocytomas stained positively for apoD, while none of 21 infiltrating astrocytomas showed similar staining. ApoD immunostaining was also seen in 9 of 14 of gangliogliomas, 4 of 5 subependymal giant cell astrocytomas (SEGAs), and a single pleomorphic xanthoastrocytomas (PXAs). By in situ hybridization, pilocytic astrocytomas, in contrast with infiltrating astrocytomas, showed widespread increased apoD expression. SAGE analysis using the NCBI database showed a higher level of expression of apoD RNA in pilocytic astrocytoma than in any of the other 94 neoplastic and non-neoplastic tissues in the database. ApoD is associated with decreased proliferation in some cell lines, and is the protein found in highest concentration in cyst fluid from benign cystic disease of the breast. ApoD might play a role in either decreased proliferation or cyst formation in pilocytic astrocytomas, gangliogliomas, SEGAs, and PXAs.

Apolipoproteins↗